Low haptoglobin in pregnancy: physiological or intravascular hemolysis?

Abstract A woman in her second trimester of pregnancy (24 weeks of gestation), diagnosed with B-cell acute lymphoblastic leukemia, received induction chemotherapy. On day six of treatment, she required transfusion with two red cell (RBC) units for anemia. Less than 12 hours later, laboratory results included elevated total bilirubin, 4.3 mg/dL [reference interval <=1.2 mg/dL], direct bilirubin, 0.3 mg/dL [reference interval <=0.3 mg/dL], haptoglobin below detection limit, <10 mg/dL [reference interval: 30 - 200 mg/dL], and normal lactate dehydrogenase (LD), 186 U/L [reference interval: 122 - 241 U/L]. These tests were ordered without any clinical suspicion for intravascular hemolysis, and upon receiving the results, the primary team consulted transfusion medicine due to concern for an acute hemolytic transfusion reaction (AHTR). After finishing the corresponding workup, the patient did not meet the Center of Disease Control (CDC) criteria for AHTR. The patient was discharged and on follow-up visits her haptoglobin increased to 15 mg/dL (25 weeks 3 days of gestation). Later, during her third trimester (27 weeks 3 day of gestation), haptoglobin increased to 142 mg/dL; LD always remained normal. Hemolysis is not associated with normal LD. Instead, some literature suggest that pregnant patients may have lower haptoglobin levels than reported in the non-pregnant population, with a nadir occurring in the second trimester. It is possible that low haptoglobin in this population may be due to the combination of hemodilution and a high estrogen state. But no literature is available that provide trimester-specific reference intervals for haptoglobin, which may lead to misinterpretation. Inspired by this case, we developed a quality improvement project to determine trimester-specific reference intervals for haptoglobin in pregnancy. Haptoglobin was tested on remnant serum samples (BD Vacutainer SST) collected from routine outpatient pregnancy patients (n=401; at least 80 samples per trimester) using Roche/Hitachi cobas c systems. Derived nonparametric reference intervals were 22-188 mg/dL for first trimester, 29-177 mg/dL for second trimester, 53-185 mg/dL for third trimester, and 30-185 mg/dL for the entire sample population. While overall reference intervals were similar, consistent with previous reports, we noticed a shift in haptoglobin distribution to the low end in the second trimester [29 (CI95% 7-35) mg/dL; median 98 mg/dL] in comparison with first trimester [22 (CI95% 15-47) mg/dL; median 113 mg/dL p = 0.34] and third trimester [29 (CI95% 7-35); median 112 mg/dL p=0.34].In the case described, the first haptoglobin below limit of detection could have been due to the combination of pregnancy (second trimester), recent red cell transfusion of RBC units (28 days old) and hyperhydration with crystalloids as part of the chemotherapy plan. This case also serves as a reminder that laboratory tests should be ordered mindfully, to aid in confirming or ruling out clinically suspected syndromes/diseases that are unlikely.